Structure-based specificity mapping of secreted aspartic proteases of Candida parapsilosis, Candida albicans, and Candida tropicalis using peptidomimetic inhibitors and homology modeling
| Autor: | Martin Hradilek, Iva Pichová, Pavel Majer, Filip Majer, L. Pavlíčková, Olga Hrušková-Heidingsfeldová, Elena Dolejší |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Proteases Peptidomimetic Clinical Biochemistry Molecular Sequence Data Antifungal drug Molecular Conformation Sequence alignment Candida parapsilosis Biochemistry Substrate Specificity Candida tropicalis Structure-Activity Relationship Aspartic Acid Endopeptidases Protease Inhibitors Homology modeling Amino Acid Sequence Candida albicans Molecular Biology Candida biology Sequence Homology Amino Acid Stereoisomerism biology.organism_classification Protein Structure Tertiary Isoenzymes |
| Zdroj: | Biological chemistry. 387(9) |
| ISSN: | 1431-6730 |
| Popis: | Secreted aspartic proteases (Saps) of pathogenicCandidaspp. represent a specific target for antifungal drug development. We synthesized a series of peptidomimetic inhibitors with different isosteric groups and modifications at individual positions and tested them with purified Saps fromC. albicans(Sap2p),C. tropicalis(Sapt1p), andC. parapsilosis(Sapp1p). The kinetic parameters indicated that all three proteases prefer binding of inhibitors containing bulky hydrophobic residues between positions P3 and P3′. The most divergent specificity was found for Sapp1p. The sequence alignment of Sap2p, Sapt1p, and Sapp1p, and homology modeling of Sapp1p with the crystal structure of Sapt1p and the complex of Sap2p with a peptidomimetic inhibitor showed that the overall folds of Sap2p, Sapt1p, and Sapp1p are similar. However, the N- and C-terminal loops formed by disulfide bonds between residues 47–53 and 258–292 are significantly shorter in Sapp1p, and a unique insertion following Tyr 129 in Sapp1p results in the formation of a loop that can interact with inhibitor residues. These Sapp1p structural differences might lead to its altered susceptibility to inhibition. |
| Databáze: | OpenAIRE |
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